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Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly

A. Ghaffar, T. Akhter, P. Strømme, D. Misceo, A. Khan, E. Frengen, M. Umair, B. Isidor, B. Cogné, AA. Khan, AL. Bruel, A. Sorlin, P. Kuentz, C. Chiaverini, AM. Innes, M. Zech, M. Baláž, P. Havrankova, R. Jech, ZM. Ahmed, S. Riazuddin, S. Riazuddin

. 2024 ; 7 (1) : 831. [pub] 20240708

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019787

Grantová podpora
R01 NS107428 NINDS NIH HHS - United States
R01NS107428 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

1st Department of Neurology Faculty of Medicine St Anne's University Hospital and CEITEC Masaryk University Brno Czech Republic

Alexander von Humboldt Fellowship Foundation Berlin 10117 Germany

Centre of Excellence in Molecular Biology University of the Punjab Lahore Pakistan

Department of Life Sciences School of Science University of Management and Technology Lahore Pakistan

Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway

Department of Medical Genetics University of Calgary Calgary Alberta Canada

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Otorhinolaryngology Head and Neck Surgery School of Medicine University of Maryland Baltimore MD USA

Department of Pediatrics CHU de Nice Fondation Lenval Nice France

Division of Pediatric and Adolescent Medicine Oslo University Hospital and University of Oslo Oslo Norway

Faculty of Biological Sciences Department of Zoology University of Lakki Marwat 28420 Khyber Pakhtunkhwa Pakistan

INSERM UMR1231 GAD Génétique des Anomalies du Développement FHU TRANSLAD Université de Bourgogne Franche Comté Dijon France

Institute for Advanced Study Technical University of Munich Lichtenbergstrasse 2 a D 85748 Garching Germany

Institute for Medical Genetics and Applied Genomics University of Tübingen Tübinge 72076 Germany

Institute of Human Genetics Technical University of Munich School of Medicine Munich Germany

Institute of Neurogenomics Helmholtz Munich Neuherberg Germany

Jinnah Burn and Reconstructive Surgery Centre Allama Iqbal Medical Research University of Health Sciences Lahore Pakistan

Nantes Université CHU Nantes Service de Génétique Médicale 44000 Nantes France

National Center of Genetics 1 rue Louis Rech L 3555 Dudelange Luxembourg

Citace poskytuje Crossref.org

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